Exercise may influence redox homeostasis and epigenetic plasticity, but longitudinal evidence linking redox-related DNA methylation to functional adaptation is limited. We examined time-dependent functional and methylation changes during 14 weeks of combined exercise training. Methods: In this single-arm longitudinal study, 45 physically inactive women participated in supervised aerobic and resistance exercise three times weekly. Functional outcomes and whole blood DNA methylation (Illumina EPIC array) were assessed at baseline and weeks 7 and 14. Repeated-measures models evaluated temporal changes, and redox-related CpGs were analyzed using limma with false-discovery-rate control. Results: Blood pressure, muscle strength, agility, and 6 min walk distance improved over time. Across different contrasts, hypomethylated CpGs were detected in CAT, SOD1, TXNRD1, TGFB1, and NFE2L2. Several CpGs remained significant after false-discovery-rate adjustment in the week-14-versus-baseline contrast. cg06295404 in SOCS1 was identified in two sequential contrasts. Methylation at cg07613405 in NFE2L2 was associated with 6 min walk distance, while exploratory public transcriptomic analyses showed concordant redox-gene expression patterns. Conclusion: Combined training was accompanied by early functional improvements and time-dependent redox-related methylation changes. Controlled studies with independent replication are needed to establish causality.
Selenium (Se) is an essential trace element for aquatic animals, but its narrow margin between nutritional requirement and toxicity necessitates precise supplementation strategies. Nano-selenium (Nano-Se) has emerged as a promising alternative, yet its dose- and time-dependent effects on the Paramisgurnus dabryanus remain poorly understood. This study employed a central composite design (CCD) within response-surface methodology (RSM) to systematically investigate the interactive effects of dietary Nano-Se concentration (0–4 mg Se/kg diet) and feeding duration (20–60 days) on growth performance, and further evaluated hepatic antioxidant parameters as well as expression profiles of 12 selenoprotein- and glutathione-metabolism-related genes. The RSM models for weight-gain rate (WGR) and specific growth rate (SGR) were highly significant (R2_Adj = 0.972 and 0.855, respectively; p < 0.001), revealing that the two factors act independently (TS term not significant, p > 0.05). Optimal growth was achieved at 1.0 mg/kg Nano-Se, with feeding duration showing a continuous positive effect on WGR (maximum at 60 d) but a plateau effect on SGR after 30 days. The medium dose (1.0 mg/kg) maintained stable antioxidant capacity and induced the strongest gene–enzyme coupling at 40 days (e.g., selenoprotein O1 (selenoo1) vs. SOD: ρ = 0.90, p < 0.001). The low dose (0.5 mg/kg) suppressed SOD and GSH-Px activities, whereas the high dose (3.0 mg/kg) disrupted positive coupling and caused an “uncoupling” phenomenon with up-regulation of antioxidant enzymes but down-regulation of transaminases. Twelve functional genes were clustered into three response modules: selenoprotein synthesis (Cluster I, including glutathione peroxidase 1 (gpx1) and tRNA-selenocysteine-1-associated protein (trnau1ap)), GSH-dependent secondary defense (Cluster II), and GSH regeneration/metabolism (Cluster III). Notably, gpx1 and other antioxidant-defense genes were prioritized under adequate Se supply, whereas trnau1ap (SECp43), a potential master switch for selenoprotein translation, was globally down-regulated under long-term high-Se exposure. In conclusion, the optimal Nano-Se supplementation for juvenile P. dabryanus is 1.0 mg/kg for 40 days, providing a theoretical basis for precision selenium nutrition in farmed fish.
Myeloperoxidase (MPO) has emerged as a promising therapeutic target for heart failure (HF) because of its pathogenic roles in oxidative stress, inflammation, and myocardial fibrosis. However, the clinical development of MPO inhibitors remains limited, and most candidates have failed in advanced trials. Here, we report the discovery of novel MPO inhibitors through an integrated computational pipeline combining machine-learning-based virtual screening with structure-based consensus docking. This approach screened ~3.1 million compounds and yielded 25 candidates for experimental evaluation. Among these, compound 16 exhibited potent MPO inhibition (IC50 = 0.297 ± 0.097 mM) and conferred significant cardioprotection in H9c2 cells subjected to oxygen-glucose deprivation, preserving cell viability to 66.19% at 25 mM. Mechanistic investigations revealed that compound 16 reduced lactate dehydrogenase release, decreased reactive oxygen species accumulation, and suppressed hypoxia/reoxygenation-induced a-SMA upregulation in a neutrophil-conditioned medium model. In addition, molecular dynamics simulations and MM-PBSA/MM-GBSA calculations suggested stable binding to MPO, primarily through p-stacking with the heme prosthetic group and hydrophobic contacts with key active-site residues. Compound 16 showed favorable predicted permeability and low predicted hERG liability, but poor metabolic stability in rat liver microsomes (T1/2 = 1.34 min), indicating that metabolic optimization is required. Collectively, this study establishes a computationally efficient strategy for MPO inhibitor discovery and identifies compound 16 as an MPO inhibitor that protects cardiomyocytes in vitro, providing a starting point for future in vivo studies aimed at heart failure therapy.
Paracoccus marcusii is an astaxanthin-synthesizing bacterium with antioxidant potential, but its mechanisms mitigating intestinal oxidative injury in fish remain unclear. Herein, we explored the protective function of P. marcusii IHA034 (CGMCC No. 25301) in juvenile Larimichthys polyactis, combining an in vivo oxidized-fish-oil challenge model and an in vitro H2O2-stimulated primary intestinal cell model. A 51-day feeding trial showed that 1.0 g/kg dietary P. marcusii supplementation improved growth performance, enhanced intestinal antioxidant enzyme activities, and restored epithelial ultrastructural damage. A strikingly high relative abundance of Paracoccus (90.50%) was detected in the gut digesta of the PM1.0 group, accompanied by reduced microbial α-diversity. In vivo intestinal transcriptomics and qPCR showed downregulated nrf2 mRNA, alongside activated complement and anti-apoptotic responses. However, P. marcusii pigment-rich crude extracts activated the Keap-1/Nrf2 pathway and rescued H2O2-induced cell injury in vitro. These findings demonstrate multi-modal protective effects of P. marcusii IHA034 and uncover contrasting Keap-1/Nrf2 regulatory patterns between in vivo intestinal tissue and in vitro cell models, providing mechanistic support for the application of this astaxanthin-producing bacterial resource in aquaculture.
Plant-derived bioactive compounds continue to attract considerable scientific interest because of their chemical diversity and their potential to modulate oxidative processes in biological and food systems [...]
